Substance P (SP) is a polypeptide, naturally occurring in various organs, notably in the central and peripheral nervous system and in the gastro-intestinal wall. Its selective distribution in the nervous system, its localization in nerve endings and its neuropharmacological actions strongly suggest that SP acts as a transmittor or modulator in certain neurons, especially in the primary sensory neurons. The following projects are in progress: 1. After completion of the mapping of SP immunoreactive cell bodies and nerve terminals in the central nervous system, attempts will be made to establish the pathways. This will be made by combining retrograde labeling techniques and immunohistochemistry. Electrothermic lesions will also be made. A mapping of SP immunoreactive neurons in the peripheral nervous system is also in progress. 2. Continued studies of a) the distribution of SP in smooth muscle organs, especially different segments and tissue layers of the gastro-intestinal tract. Other regions of interest are the urinary tract, gall bladder and the smooth muscles of the bronchi, b) the chemical characteristics of the SP activity found in tissue extracts and body fluids, c) the enzymatic destruction of SP in tissue extracts, notably in blood and cerebrospinal fluid, d) the release of SP from various organs, especially in connection to stimulation of sensory nerves, e) identification of specific tissue receptors binding SP. 3. Continued studies on the agonist-antagonist activities of SP.